Comparative analysis of DNA mutations in
            <i>lacI</i>
            transgenic mice with age

Lee, Annette T.; DeSimone, Christine; Cerami, Anthony; Bucala, Richard

doi:10.1096/fasebj.8.8.8181674

Cited by 67 publications

(30 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, if the same mutation is observed in multiple cells, it cannot be determined if the mutation results from multiple independent events (e.g., at a mutation hot spot) or clonal expansion. Thus, many of the studies analyzing the accumulation of mutant cells with age either do not differentiate between the contribution of independent mutation events and clonal expansion [46,47,49,65] or completely remove the contribution of clonal expansion by specifically analyzing only independent mutation events [43,44]. Our previous studies [51], combined with the results presented here, indicate that clonal expansion contributes significantly to the overall increase in recombinant pancreatic cells with age.…”

Section: Discussionmentioning

confidence: 86%

Tissue-specific differences in the accumulation of sequence rearrangements with age

et al. 2008

View full text Add to dashboard Cite

Mitotic homologous recombination (HR) is a critical pathway for the accurate repair of DNA double strand breaks (DSBs) and broken replication forks. While generally error-free, HR can occur between misaligned sequences, resulting in deleterious sequence rearrangements that can contribute to cancer and aging. To learn more about the extent to which HR occurs in different tissues during the aging process, we used Fluorescent Yellow Direct Repeat (FYDR) mice in which an HR event in a transgene yields a fluorescent phenotype. Here, we show tissue-specific differences in the accumulation of recombinant cells with age. Unlike pancreas, which shows a dramatic 23-fold increase in recombinant cell frequency with age, skin shows no increase in vivo. In vitro studies indicate that juvenile and aged primary fibroblasts are similarly able to undergo HR in response to endogenous and exogenous DNA damage. Therefore, the lack of recombinant cell accumulation in the skin is most likely not due to an inability to undergo de novo HR events. We propose that tissue-specific differences in the accumulation of recombinant cells with age result from differences in the ability of recombinant cells to persist and clonally expand within tissues.

show abstract

Section: Discussionmentioning

confidence: 86%

Tissue-specific differences in the accumulation of sequence rearrangements with age

et al. 2008

View full text Add to dashboard Cite

show abstract

“…For example, splenic DNA from lacI transgenic mice was analyzed for mutations at various ages from birth to 24 months old, and a gradual, linear, 4-fold increase in mutation frequency was noted with increasing age (28). In humans, a decrease in DNA-repair capacity of UV products has been demonstrated in peripheral lymphocytes with increased age (29).…”

Section: Discussionmentioning

confidence: 99%

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Walter

Intano

McCarrey

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

125

121

View full text Add to dashboard Cite

Five percent of live-born human offspring will have a genetic disorder. Of these, 20% are because of germ-line de novo mutations. Several genetic diseases, such as neurofibromatosis and Duchenne muscular dystrophy, are associated with a high percentage of de novo germ-line mutations. Until recently, a direct analysis of spontaneous mutation frequencies in mammalian germ cells has been prevented by technical limitations. We have measured spontaneous mutation frequencies in a lacI transgene by using enriched populations of specific spermatogenic cell types. Similar to previously published results, we observed a lower mutation frequency for seminiferous tubule cell preparations, which contain all stages of spermatogenesis, relative to somatic tissues. We made the unexpected observation of a decline in mutation frequency during spermatogenesis, such that the mutation frequencies of type B spermatogonia and all subsequent stages of spermatogenesis are lower than the frequency for primitive type A spermatogonia. In addition, spermatogenic cells from old mice have significantly increased mutation frequencies compared with spermatogenic cells from young or middle-aged mice. Finally, the mutation frequency was observed to increase during spermiogenesis in postreplicative cell types when spermatogenic cells were obtained from old mice.From a genetic perspective, germ cells are profoundly different from somatic cells because they carry the genetic information that will direct the development of the next generation, not simply the next daughter cell. Thus, safeguarding the integrity of germ-line DNA might provide evolutionary advantages. Indeed, in mice, mutation frequencies obtained from mixed populations of germ cells are lower than for somatic tissues (1). This was demonstrated by using a transgenic system in which the bacteriophage genome carrying the lacI repressor gene and the ␣lacZ gene from the prokaryotic lac operon was introduced into the mouse genome as a transgene. DNA was recovered from genomic DNA preparations by packaging and used to infect a strain of Escherichia coli carrying a lacZ (␤-galactosidase) gene, but lacking a functional lacI gene. Mutation of the lacI gene renders a blue plaque on agarose containing the chromogenic substrate 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside (X-gal). In contrast, other studies using a lacI transgenic mouse (2) or a lacZ transgenic mouse (3) did not report a significant difference in mutation frequencies for spermatogenic cells compared with somatic cells.Although provocative, interpretation of the results demonstrating a lower mutation frequency for male germ cells is complicated by the fact that adult seminiferous tubules contain a mixture of spermatogenic cell types encompassing all stages of spermatogenesis. Spermatogonia serve as the stem cells for spermatogenesis and undergo mitotic divisions that give rise to cells that will either retain their identity as spermatogonia to maintain the stem cell population or enter meiosis to become primary spermatocy...

show abstract

“…The apoptotic response exhibited by a number of immortalized cells and cancer cells with mutated p53 further complicates the understanding of the p53 mediated apoptotic pathway. CHO cells have a mutated p53 and cannot activate transcription of p21 and Bax genes that are involved in G1 arrest and apoptosis (Lee et al, 1994;Miyashita et al, 1995). The loss of this G1 check point is due to a mutation in p53 gene of CHO cells that changes the amino acid threonine 211 to lysine 211 (Lee et al, 1997).…”

Section: The Apoptotic Response In Human Cs-b Cells Is Dependent On P53mentioning

confidence: 99%

Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis

Proietti-De-Santis

et al. 2000

Oncogene

View full text Add to dashboard Cite

Cockayne syndrome (CS) is a human autosomal recessive disorder characterized by many neurological and developmental abnormalities. CS cells are defective in the transcription coupled repair (TCR) pathway that removes DNA damage from the transcribed strand of active genes. The individuals su ering from CS do not generally develop cancer but show increased neurodegeneration. Two genetic complementation groups (CS-A and CS-B) have been identi®ed. The lack of cancer formation in CS may be due to selective elimination of cells containing DNA damage by a suicidal pathway. In this study, we have evaluated the role of the CSB gene in UV induced apoptosis in human and hamster cells. The hamster cell line UV61 carries a mutation in the homolog of the human CSB gene. We show that both human CS-B and hamster UV61 cells display increased apoptotic response following UV exposure compared with normal cells. The increased sensitivity of UV61 cells to apoptosis is complemented by the transfection of the wild type human CSB gene. In order to determine which functional domain of the CSB gene participates in the apoptotic pathway, we constructed stable cell lines with di erent CSB domain disruptions. UV61 cells were stably transfected with the human CSB cDNA containing a point mutation in the highly conserved glutamic acid residue in ATPase motif II. This cell line (UV61/ pc3.1-CSBE646Q) showed the same increased apoptosis as the UV61 cells. In contrast, cells containing a deletion in the acidic domain at the N-terminal end of the CSB protein had no e ect on apoptosis. This indicates that the integrity of the ATPase domain of CSB protein is critical for preventing the UV induced apoptotic pathway. In primary human CS-B cells, the induction and stabilization of the p53 protein seems to correlate with their increased apoptotic potential. In contrast, no change in the level of either p53 or activation of mdm2 protein by p53 was observed in hamster UV61 cells after UV exposure. This suggests that the CSB dependent apoptotic pathway can occur independently of the transactivation potential of p53 in hamster cells.

show abstract

Comparative analysis of DNA mutations in lacI transgenic mice with age

Cited by 67 publications

References 17 publications

Tissue-specific differences in the accumulation of sequence rearrangements with age

Tissue-specific differences in the accumulation of sequence rearrangements with age

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis

Contact Info

Product

Resources

About